Echinocandin compounds containing a hemiaminal functionality are generally prone to ring opening at the aminal bond, especially at elevated temperatures. In addition, the amorphous forms of the compounds are sensitive to both humidity and temperatures above −10° C. the amorphous material is not stable above freezer temperatures. This not only effects the shelf-life of the drug in bulk form but also makes it more difficult to handle the compounds in an industrial process.
One approach to eliminate the ring-opening at the aminal bond is to remove or functionalize the hydroxy group of the hemiaminal function; however, this requires an additional synthetic step. Even though this is a very effective way to increase stability of the modified compound, any additional steps in a manufacturing process reduce productivity, increase potential for waste and increase cost.
U.S. Pat. No. 4,876,241 discloses the use of a sugar as a stabilizer in biological and pharmaceutical products; however, the process is directed to the stabilization of the products during thermal inactivation of viral and bacterial contaminants in solution. The sugar is removed after the thermal inactivation process. Consequently, this process doesn't address the long-term stability of the product.
The stabilization effects of sugars in a thermal process have been shown. For example, the effects of sugars, pH and calcium on the thermal denaturation of whey proteins is discussed in Ibrahim et al. Egyptian J.0. Dairy Sci., 23:177–188 (1995). Like the previous reference, the stabilizing effects were realized in a liquid form. Neither reference suggests that stability could be enhanced by incorporation of a carbohydrate into the crystalline form of a compound.
In addition to thermal instability, the lipopeptide compounds, such as the echinocandins, are also known to have very poor water solubility (<0.1 mg/ml) which makes them particularly difficult to formulate for parenteral (ip) applications and complicates the purification of the materials. Generally, amorphous materials are more difficult to purify than crystalline materials.
Therefore, there is a need for improved thermal stability and water solubility of echinocandin compounds without effecting bioavailability or making structural changes to the compound as well as providing a means to further purify the echinocandin.